WO2023284426A1

WO2023284426A1 - Anti-gout celery seed-flos sophorae immaturus extract and febuxostat pharmaceutical composition, and use thereof

Info

Publication number: WO2023284426A1
Application number: PCT/CN2022/095120
Authority: WO
Inventors: 高永良; 秦华; 张强; 张铁军; 杨红军; 杨文斌
Original assignee: 北京天衡军威医药技术开发有限公司
Priority date: 2021-07-13
Filing date: 2022-05-26
Publication date: 2023-01-19
Also published as: CN115607588B; CN115607588A

Abstract

An anti-gout celery seed-flos sophorae immaturus extract and febuxostat pharmaceutical composition, and a use thereof. The celery seed-flos sophorae immaturus extract is a celery seed and flos sophorae immaturus alcohol extract at a weight ratio of 2:1-4:1. The celery seed-flos sophorae immaturus extract is combined with a small dose of febuxostat and used for treating hyperuricemia or gout in mammals or humans, and toxic side effects of febuxostat can be reduced.

Description

An anti-gout medicinal composition of celery locust extract and febuxostat and its application

technical field

The invention relates to the technical field of medicines for treating gout or hyperuricemia, in particular, the invention relates to medicines or combination kits for treating gout and/or hyperuricemia in humans. The present invention also relates to the combined medicine and pharmaceutical application of the celery locust extract and febuxostat for treating gout or hyperuricemia.

Background technique

Gout and hyperuricemia are common metabolic diseases and important public health problems worldwide.

Gout is a group of metabolic diseases that lead to elevated blood uric acid due to purine metabolism disorders. Therefore, an important cause of gout is that the patient's blood uric acid level exceeds the normal value, and before the onset, it is often accompanied by an inducing cause. Such as overeating before the onset, excessive consumption of high-purine foods such as broth, seafood, etc., frequent drinking, smoking, overwork, and exposure to wind and cold. Under a normal purine diet, if the fasting blood uric acid level is higher than 420 μmol/L twice on different days, it is called hyperuricemia.

The clinical natural history of gout is divided into four stages as follows:

(1) Asymptomatic period

At this time, the blood uric acid is higher than the normal level, so it is called hyperuricemia. During this period, patients usually have no clinical manifestations, no joint pain, and no other discomforts, commonly known as the silent killer. However, the damage of high uric acid to the body has begun to appear, and slowly damage to blood vessels and kidneys in the patient's body. During this period, the concentration of uric acid in the serum of patients will increase, but clinical symptoms such as arthritis symptoms, tophi, or uric acid stones do not appear. Some male patients will have this situation during puberty, and it may be related to family history, while female patients are more likely to appear during menopause. Asymptomatic hyperuricemia may exist throughout life, but it may also turn into acute gouty arthritis or kidney stones. Most patients with asymptomatic hyperuricemia will first develop gout symptoms before changing to other conditions , but note that about 10% to 40% of patients will first develop symptoms of kidney stones.

(2) Acute Arthritis Phase

During this period, patients will experience severe pain in the affected joints. In the early stage of the disease, a single joint is more common (accounting for 90%), and about half of them occur in one metacarpal joint. Therefore, the patient suffers from unbearable pain and cannot put on shoes. , often come to see a doctor wearing slippers, but later on, it is likely to invade multiple joints, and sometimes it may only invade other parts. The common parts of gout include big toe, instep, ankle, heel, knee, wrist, fingers and so on. Elbow and other parts, but other parts can also occur.

Generally speaking, gout patients will start to experience severe pain and joint inflammation at night, and sometimes fever symptoms at the same time. The onset of this kind of situation often occurs after eating too much, especially after a banquet, drinking, drugs, trauma Or after surgery, and sometimes after an ankle sprain, especially if you're dehydrated. Clinically, there may be no abnormality before the patient goes to bed, but the severe pain caused by gout attack may wake the patient up from sleep, and severe redness, swelling and heat pain will appear in the affected joints, which is unbearable pain. Symptoms will progress from mild to severe, and the chills and tremors will also increase. At the most painful time, it will be like tearing, which is unbearable, and then the symptoms will gradually decrease.

(3) Intermission period

The intermission period refers to the period during which symptoms disappear between two attacks, that is, the patient does not have any symptoms clinically. The length of the intermittent period varies, and may last for one or two days to several weeks, and then there will be another attack. A very small number of patients with gout only attack once in their lives and no longer have symptoms, but the vast majority of patients will relapse. After repeated attacks, it tends to be polyarticular, the attacks are more serious, the attack period is longer, and it is accompanied by fever.

(4) Chronic Arthritis Period

Gout attacks for a long time, without treatment or irregular treatment, uric acid crystals will deposit in the cartilage, synovial membrane, and soft tissues in the body, forming tophi. Moreover, the higher the concentration of uric acid in the blood and the longer the duration of the disease, the more tophi may be deposited, leading to chronic gouty arthritis, sometimes affecting blood vessels and kidneys, causing severe renal failure, making the kidney disease more serious, and This creates a vicious cycle where it is difficult to excrete uric acid, resulting in more tophi deposits.

There are often many places where tophi is deposited, including the pinnae, hands, elbows, Achilles tendons, ankles or toes. Sometimes it will cause local ulcers, which are not easy to heal, and even require amputation. Serious patients can cause joint deformation or chronic symptoms. When the foot deformation is serious, it may cause serious problems for the patient to wear shoes. In addition, the risk of kidney stones increases with the increase of serum uric acid concentration, and it often causes kidney disease. Hemodialysis may be required after kidney failure, which is also one of the main causes of death in gout patients.

In addition, gout is common in obese, hypertriglyceridemia and hypertensive patients. Obese people will increase uric acid production and decrease excretion, causing hyperuricemia and gout. If these diseases appear clinically at the same time, it may also cause uncontrollable situations, so attention should be paid to the evaluation during the examination.

Hyperuricemia and gout cannot be equated. High blood uric acid is not necessarily gout, but gout patients must have high blood uric acid. Clinically, it is generally only called gout when arthritis occurs. 5%-12% of hyperuricemia can develop into gout. Therefore, when doctors diagnose gout clinically, in addition to paying attention to high uric acid levels, they also need to include the onset of acute monoarthritis, and even the discovery of urate crystals, so that they can diagnose gout under the guidance of specialists. When gout attacks, some patients often have uric acid and blood uric acid in the normal range due to body compensation.

With rapid economic development and significant changes in people's lifestyles, the prevalence of hyperuricemia and gout in China has increased significantly. According to the latest research results, patients with hyperuricemia have accounted for 13.3% of the total population, especially in economically developed cities and coastal areas, the prevalence of hyperuricemia is as high as 5%-23.5%. The prevalence of gout is 1% to 3%, and it is increasing year by year. According to the 2017 "China Gout Status Report", the number of hyperuricemia patients in my country has reached 170 million, of which more than 80 million gout patients are rapidly increasing at an annual growth rate of 9.7%.

Another epidemiological feature of gout is that the age of onset is getting younger. According to the stage data of the National Rheumatology Data Center (CRDC) network registration and follow-up research, based on 6,814 effective cases of gout patients in 100 hospitals in 27 provinces, municipalities, and autonomous regions across the country, the average age of gout patients in my country is 48.28 years old, which is gradually increasing. younger. A survey by the China-Japan Friendship Hospital found that in less than 20 years, the average age of onset of gout patients has dropped by 6.3 years, and the number of people suffering from gout for the first time before the age of 40 has increased by 26.3%.

At present, gout has become the second largest metabolic disease in my country after diabetes, and it is a systemic disease involving multi-system functions. Many evidences show that hyperuricemia and gout are independent risk factors for diseases such as chronic kidney disease, hypertension, cardiovascular and cerebrovascular diseases, and diabetes, and are independent predictors of premature death. Taking chronic kidney disease (CKD) as an example, for every 1 mg/dL increase in blood uric acid level in patients with stage 3-4, the risk of cardiovascular death increases by 16%, and the risk of all-cause death increases by 17%. Gouty nephropathy with a course of more than 10 years can easily lead to renal colic, hematuria, renal failure and uremia, and ultimately necessitates a kidney transplant to sustain life. About 15% of patients die from renal failure.

In addition to the involvement of multiple system functions, gout also leads to joint deformities, which seriously affects the patient's limb function, which in turn causes huge obstacles and difficulties in daily life, and makes the patient lose the ability to work. There have been news reports of gout patients applying for disability certificates. Hyperuricemia/gout also affects the sexual function of male patients. In a study of middle-aged men in a hospital rheumatology department, 76% of gouty men had erectile dysfunction (ED), compared with 51% of normal men. Gouty men have a higher rate of organic ED than other men. ED in these men was likely due to hyperuricemia, which is elevated uric acid years before the onset of gout symptoms.

The treatment of gout with hyperuricemia is generally drug therapy and general treatment. The common therapeutic drugs in clinical practice include: non-steroidal anti-inflammatory drugs, colchicine, and glucocorticoids in the acute attack phase, and febuxostat, allopurinol, and benzbromarone in the remission phase of gout. For general treatment, patients should eat a low-purine diet, take baking soda tablets to alkalize the urine, drink plenty of water, exercise properly, and keep warm in the joints to promote the excretion of uric acid and prevent gout from recurring.

At present, gout cannot be cured. The core of the treatment method is to reduce the blood uric acid level first, so as to reduce the attack of acute arthritis, prevent urate deposition, prevent the formation of tophi and renal function damage. Uric acid-lowering drugs commonly used in clinical practice are mainly divided into two categories: inhibiting uric acid production and promoting uric acid excretion.

1. Drugs that inhibit the production of uric acid play a role in lowering uric acid by inhibiting xanthine oxidase.

① The initial dose of allopurinol is 50mg once, 1-2 times a day, and can be increased by 50-100mg every week to 200-300mg a day, divided into 2-3 times. Measure blood and urine uric acid levels every 2 weeks. If they have reached normal levels, do not increase them. If they are still high, they can be increased. But the maximum daily dose should not exceed 600mg. Side effects: gastrointestinal reactions, leukopenia, thrombocytopenia, anemia, bone marrow suppression. Others include hair loss, fever, lymphadenopathy, liver toxicity, interstitial nephritis and allergic vasculitis. It can also lead to exfoliative dermatitis, toxic epidermal necrolysis, severe erythema multiforme drug eruption, drug hypersensitivity syndrome, liver function damage, renal function damage, etc.

The structural formula of allopurinol is as follows:

② The initial dose of febuxostat is 20 mg once a day, and the dosage can be gradually increased according to the blood uric acid value after 4 weeks of administration, with each increment of 20 mg, and the maximum daily dose is 80 mg. Side effects: cardiovascular risk, abnormal liver function, nausea, arthralgia, rash.

The structural formula of febuxostat is as follows:

2. Drugs that promote uric acid excretion

① Adults take benzbromarone orally 50mg (one tablet) each time, once a day, after breakfast. Check the patient's serum uric acid concentration after taking the medicine for 1 week, or take 100mg (two tablets) orally per day at the beginning of treatment, take it after breakfast, and change to 50mg (one tablet) per day when the blood uric acid drops to the normal range. Side effects: liver toxicity, uric acid stones, liver and kidney stones. ②Probenecid and sulfinpyrazone can only be used in patients with normal renal function, and liver damage is more common.

The disadvantage of the prior art is that in the field of clinical treatment of gout and hyperuricemia, drugs that inhibit uric acid production, such as febuxostat and allopurinol, are used in a considerable amount. Clinical studies over the years have shown that although febuxostat and allopurinol can reduce blood uric acid levels, the disadvantages are also obvious:

1) Limited curative effect

The efficacy of febuxostat and allopurinol monotherapy is limited. Even after increasing the dose to a larger amount, there are still millions of patients whose condition cannot be controlled every year, and the blood uric acid does not reach the standard (less than 360 μmol/L).

2) The safety is poor, and the adverse reactions will be aggravated after increasing the dose.

Both febuxostat and allopurinol monotherapy have serious side effects, and they are all dose-related. The greater the dose, the greater the side effects.

The main adverse reaction of febuxostat is cardiovascular toxicity. In randomized controlled studies, compared with allopurinol, patients treated with febuxostat had a higher probability of cardiovascular thrombotic events (including cardiovascular death, non-fatal myocardial infarction, non-fatal stroke), among which Febuxostat was 0.74/100 patient-years (95% CI: 0.36-1.37), and allopurinol was 0.60/100 patient-years (95% CI: 0.16-1.53). A causal relationship between febuxostat and cardiovascular thrombotic events has not been established. Pay attention to monitor the symptoms and signs of myocardial infarction and stroke when taking medicine.

In the CARES study targeting gout patients with associated cardiovascular disease, there was a higher incidence of cardiovascular death in the febuxostat group compared with the allopurinol group. Therefore, gout patients with cardiovascular disease should use this product with caution. If the clinician evaluates that the benefits of using this product outweigh the risks, the patients should pay close attention to the deterioration of existing cardiovascular diseases and new cardiovascular diseases during the use of this product. Once the above situations occur, medical treatment should be carried out in time.

On November 15, 2017, the US FDA issued a cardiovascular risk warning for febuxostat, stating that compared with allopurinol, febuxostat increases the risk of heart-related all-cause death. Although 56.6% of the patients in the clinical data released by the US FDA discontinued treatment, 45% of the patients were lost to follow-up, and there was a major bias, but this still reminds that in the process of clinical application, it is necessary to monitor the occurrence of cardiovascular diseases in patients and pay attention to cardiovascular risks For the prevention of patients, for patients with high cardiovascular risk, medication needs to fully weigh the pros and cons. In the latest treatment guidelines in the United States, febuxostat has been reduced to the second-line treatment drug, and for gout patients with cardiovascular disease, it is recommended to replace febuxostat with other urate-lowering drugs. In the revised U.S. label, febuxostat is only used in patients who cannot tolerate allopurinol or whose use is not recommended.

Allopurinol may cause adverse reactions ranging from mild rash (MPE) to severe skin adverse reactions (SCAR). Specifically Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and rare but potentially life-threatening allopurinol allergy Syndrome (AHS). AHS is a rare adverse reaction, but special attention should be paid to the use of it in the Chinese population (the incidence rate in Taiwan, China is 2.7%). Once it occurs, the fatality rate is as high as 30%. It has been confirmed that the occurrence of AHS is significantly correlated with HLA-B*5801, and the frequency of carrying this genotype in the Han population is 10%-20%. Therefore, for HLA-B*5801-positive patients, domestic and foreign guidelines do not recommend the use of allopurinol.

my country's traditional Chinese medicine has a long history of preventing and treating gout. After thousands of years of clinical practice, it has accumulated rich medical experience and formed a systematic theoretical system and treatment methods. The curative effect and safety of Western medicine for lowering uric acid are not ideal, but the clinical needs are urgent, the inventor invented a pure Chinese medicine preparation, according to the theory of traditional Chinese medicine, celery seed and Sophora japonica were formulated (Chinese patent ZL201610313303 .8). Celery seed clears away heat and annoyance, promotes water and reduces swelling, disperses Qi, reduces swelling, and unblocks stagnation. Huai Mi is good at clearing heat and dampness, cooling blood to stop bleeding, and can clear away heat in blood. The combination of the two medicines can search for rheumatism-heat toxins in the meridians and joints, thereby treating the syndrome of wind pain and spasm in the past. It is a kind of anti-gout traditional Chinese medicine that treats both symptoms and root causes. Under the guidance of pharmacodynamics, the applicant systematically optimized the ratio of celery seed and sophora japonica, and conducted pharmacodynamic experiments and clinical studies on the compound extract. The results showed that the compound was reasonable in compatibility and had synergistic Sustained effect of lowering uric acid. Because it is a product of the same origin as medicine and food, it has basically no toxic and side effects, and it also shows good druggability, and can be made into medicines in the form of tablets, capsules, and granules.

Like most traditional Chinese medicines, celery locust extract has a slow onset, mild effect, and basically no toxic side effects. However, for acute attacks of gout and insufficient control of temporary fluctuations in blood uric acid levels caused by diet, it needs to be overcome before it can be expanded. The scope of application can better meet the clinical needs.

At present, there is an urgent clinical need for a drug or drug combination that can treat both symptoms and root causes with stronger and longer-lasting uric acid-lowering effect and less toxic side effects.

Contents of the invention

In order to overcome the shortcomings of the curative effect and safety of existing western medicine and traditional Chinese medicine for lowering uric acid, the technical solution of the present invention is to provide a kind of pharmaceutical composition of Acacia celery extract and febuxostat that treats both the symptoms and root causes of gout, and is characterized in that The pharmaceutical composition is composed of 225-2250mg celery extract, 5-20mg febuxostat and a pharmaceutically acceptable carrier, wherein the celery extract is celery with a weight ratio of 2:1-4:1 Alcoholic extracts of celery seeds and sophora flower bud.

Preferably, a pharmaceutical composition of Acacia celery extract and febuxostat for treating both symptoms and root causes of gout, characterized in that the pharmaceutical composition consists of 450-1800mg of Acacia celery extract, 10-20mg of febuxostat and a pharmaceutically acceptable carrier, wherein the celery locust extract is the alcohol extract of celery seeds and sophora flower bud in a weight ratio of 2:1-4:1.

It is particularly preferred that a pharmaceutical composition of Acacia celery extract and febuxostat for treating both symptoms and root causes of gout is characterized in that the pharmaceutical composition consists of 900-1350mg of Acacia celery extract, 10-20mg of febux It consists of a pharmaceutically acceptable carrier, wherein the celery locust extract is the alcohol extract of celery seeds and sophora flower bud in a weight ratio of 2:1-4:1.

The present invention further provides a kit for treating gout and/or hyperuricemia in mammals or humans, the kit is composed of 225-2250mg celery locust extract, 5-20mg febuxostat and a pharmaceutically acceptable carrier and The drug instructions consist of the extract of celery locust being the alcohol extract of celery seeds and sophora flower bud with a weight ratio of 2:1-4:1.

Preferably, the present invention provides a kit for treating gout and/or hyperuricemia in mammals or humans. The carrier and the drug instructions, wherein the celery locust extract is the alcohol extract of celery seeds and sophora flower bud in a weight ratio of 2:1-4:1.

Particularly preferably, the present invention further provides a kit for treating gout and/or hyperuricemia in mammals or humans, the kit is composed of 900-1350mg celery locust extract, 10-20mg febuxostat and a drug instruction , wherein the celery locust extract is an alcoholic extract of celery seeds and sophora flower bud in a weight ratio of 2:1–4:1.

The present invention also provides the use of a pharmaceutical composition of Acacia celery extract and febuxostat in the preparation of medicines for treating gout and/or hyperuricemia in mammals or humans, wherein the pharmaceutical composition consists of 225-2250mg of Acacia celery Extract, 5-20mg of febuxostat and a pharmaceutically acceptable carrier, wherein the celery extract is the alcohol extract of celery seed and sophora japonica with a weight ratio of 2:1-4:1.

In other words, the present invention provides a pharmaceutical composition of Acacia celery extract and febuxostat, which is used to treat gout and/or hyperuricemia in mammals or humans, wherein the pharmaceutical composition consists of 225- 2250mg of Acacia celery extract, 5-20mg of febuxostat and a pharmaceutically acceptable carrier, wherein the Acacia celery extract is celery seed and Sophora japonica alcohol extract with a weight ratio of 2:1-4:1.

In other words, the present invention provides a method for treating gout and/or hyperuricemia in mammals or humans in combination with acacia extract and febuxostat, comprising administering an effective dose of acacia extract and febuxostat to the patient , the daily dose of febuxostat tablets ranges from 5 mg to 20 mg, and the daily dose of celery locust extract in terms of extracts ranges from 225 mg to 2250 mg.

The present invention also provides a combination of acacia extract and febuxostat in the preparation of medicines for the treatment of gout and/or hyperuricemia in mammals or humans, wherein the extract of acacia is in a weight ratio of 2: 1–4:1 celery seed and sophora japonica alcohol extract, preferably the daily dose of febuxostat tablet ranges from 5 mg to 20 mg, and the daily dose of celery locust extract in terms of extract ranges from 225 mg to 2250 mg .

In other words, the present invention provides a combination of celery locust extract and febuxostat for use in the treatment of gout and/or hyperuricemia in mammals or humans, wherein the celery locust extract has a weight ratio of 2 :1–4:1 celery seed and sophora japonica alcohol extract, preferably the daily dosage range of the febuxostat tablet is 5 mg to 20 mg, and the daily dosage range of the celery locust extract is 225 mg to 20 mg in terms of extract. 2250mg.

In other words, the present invention provides a method for treating gout and/or hyperuricemia in a mammal or a human, comprising administering to a patient an effective amount of a combination of acacia extract and febuxostat, wherein the acacia extract It is the alcohol extract of celery seed and sophora japonica with a weight ratio of 2:1-4:1, preferably the daily dosage range of the febuxostat tablet is 5mg to 20mg, and the daily dose of celery locust extract is calculated by extract. The dose ranges from 225 mg to 2250 mg, and the extract of celery locust and febuxostat are administered simultaneously, sequentially or separately.

The present invention also provides the use of a locust extract in the preparation of a drug for improving febuxostat's treatment effect on gout and/or hyperuricemia and/or reducing its toxic and side effects, wherein the extract of locust The substance is the alcohol extract of celery seed and sophora japonica with a weight ratio of 2:1–4:1, preferably, the daily dosage range of the febuxostat tablet is 5mg to 20mg, and the celery locust extract is calculated as the extract The daily dosage range of 225mg to 2250mg.

In other words, the present invention provides an extract of Acacia celery, which is used to improve the therapeutic effect of febuxostat on gout and/or hyperuricemia and/or reduce its toxic and side effects, wherein the extract of Acacia celery is The weight ratio is 2:1-4:1 of celery seed and sophora japonica alcohol extract, preferably, the daily dose range of the febuxostat tablet is 5 mg to 20 mg, and the daily dose of celery locust extract in terms of extract Dosage ranges from 225mg to 2250mg.

In other words, the present invention provides a method for improving the therapeutic effect of febuxostat on gout and/or hyperuricemia and/or reducing its toxic and side effects, which includes administering effective doses of acacia extract and febuxostat to patients wherein the extract of Acacia celery is 2:1-4:1 weight ratio of celery seed and sophora alcohol extract, preferably the daily dosage range of the febuxostat tablet is 5mg to 20mg, The daily dosage range of the extract of celery locust is 225 mg to 2250 mg in terms of extract, and the extract of celery locust and febuxostat are administered simultaneously, sequentially or separately.

The toxic and side effects of febuxostat can be cardiovascular toxicity, especially cardiovascular thrombotic events (including cardiovascular death, non-fatal myocardial infarction, non-fatal stroke), as well as stomach discomfort, abnormal liver function, Abnormal renal function, etc.; especially cardiovascular toxicity.

The celery locust extract of the present invention is obtained according to the formula and method of Chinese patent ZL201610313303.8.

Celery seed and Sophora japonica alcohol extract of the present invention is the extract of celery seed or Sophora japonica in alcohol solvent, and the ratio of celery seed and Sophora japonica in the Sophora celery extract is 2:1～4: 1. The alcoholic solvent can be C1～C4 alcoholic solvent, preferably methanol, ethanol, isopropanol, n-butanol, or an aqueous alcoholic solution, and the concentration of the aqueous alcoholic solution is preferably 50% by volume ~80%. The extract of Acacia celery in the present invention can be in the form of granules, tablets, dropping pills, or capsules, preferably capsules.

Furthermore, a new pharmaceutical composition was invented: Acacia celery extract + small dose febuxostat pharmaceutical composition.

The daily dose of febuxostat tablets ranges from 5 mg to 20 mg. A further preferred ratio is 10 mg to 20 mg.

The daily dosage range of celery locust extract is 225mg to 2250mg (based on extract), the preferred daily dosage range is 450mg to 1800mg (based on extract), and the further preferred daily dosage range is 900mg to 1350mg (based on extract) ), the most preferred daily dosage of celery locust extract is 900 mg (in terms of extract).

As an embodiment of preferred combined use, the daily dosage of the extract of celery locust is 900 mg, and the daily dosage of febuxostat is 5 mg-20 mg. Further preferably, first give the patient a daily dose of celery locust extract of 900 mg + a daily dose of febuxostat of 20 mg for a period of time, so that the blood uric acid level is rapidly reduced to a reasonable level, and then give the patient a daily dose of celery locust extract of 900 mg + febuxostat daily Dose 10mg, keep blood uric acid level stable and not rebound. For some patients with stable blood uric acid levels, the daily dose of celery locust extract 900 mg + febuxostat daily dose 5 mg can be selected as the maintenance dose.

As the first embodiment of the present invention, the present invention provides a combination of combined administration. The extract of celery locust and febuxostat can be made into solid preparation compositions, such as tablets, capsules, granules and other dosage forms, and provided to patients in the form of combined medication. Preferably, the extract of celery locust is made into capsules by adding appropriate pharmaceutically acceptable excipients, and febuxostat is made into tablets or capsules. The forms of the combined medication include but not limited to simultaneous administration, sequential administration, interval administration, alternate administration and other forms of combined administration.

In the form of combined medication, the daily dosage range of febuxostat is 5mg to 20mg; the daily dosage range of celery locust extract is 225mg to 2250mg (extract), and the preferred daily dosage range is 450mg to 1800mg (extract In terms of extracts), the further preferred daily dosage range is 900 mg to 1350 mg (in terms of extracts), and the most preferred daily dose of the extract of Acacia celery is 900 mg (in terms of extracts).

As the second embodiment of the present invention, the present invention provides a combination medicine box product.

The present invention provides a kit for treating gout and/or hyperuricemia in mammals and/or humans, the kit consists of 225-2250mg celery extract, 5-20mg febuxostat and a pharmaceutically acceptable carrier And the composition of the drug instructions, wherein the extract of celery locust is the extract of celery seed and sophora japonica alcohol with a weight ratio of 2:1-4:1. Further, the kit is composed of 450-1800mg of celery locust extract, 10-20mg of febuxostat, a pharmaceutically acceptable carrier and a drug instruction, wherein the weight ratio of celery locust extract is 2:1-4:1 or, the kit consists of 900–1350mg celery extract, 10-20mg febuxostat and a pharmaceutically acceptable carrier and drug instructions, wherein the celery extract is Alcohol extracts of celery seed and sophora japonica in a weight ratio of 2:1–4:1.

In the kit, the extract of Acacia celery and febuxostat can be made into solid preparation compositions, such as tablets, capsules, granules and other dosage forms, and provided to patients in the form of a complete combination kit. In terms of dosage forms, it is preferable to add appropriate pharmaceutically acceptable excipients (carriers) to the celery locust extract to make capsules, and add appropriate pharmaceutically acceptable excipients (carriers) to febuxostat to make tablets or capsules. The daily dosage range of the febuxostat equivalent of the two preparations in the combination kit is 5 mg to 20 mg; the daily dosage range of the celery locust extract is 225 mg to 2250 mg (calculated as an extract), and the preferred daily dosage range is 450 mg to 1800 mg ( In terms of extract), the further preferred daily dosage range is 900 mg to 1350 mg (in terms of extract), and the most preferred daily dose of the extract of Acacia celery is 900 mg (in terms of extract).

As a preferred embodiment of the aforementioned combination kit, the daily dosage of the preparation of the celery locust extract is 900 mg, and the daily dosage of the febuxostat preparation is 5 mg-20 mg. It is further preferred that after giving the patient a daily dose of 900 mg of celery locust extract + febuxostat daily dose of 20 mg combination kit for a period of time, the blood uric acid level is quickly reduced to a reasonable level, and then the patient is given a daily dose of celery locust extract The combination kit of 900mg + febuxostat daily dose of 10mg keeps the blood uric acid level stable and does not rebound. For some patients with stable blood uric acid levels, the maintenance dose can be a combination kit with a daily dose of celery extract 900 mg + a daily dose of febuxostat 5 mg.

As the third embodiment of the present invention, the present invention provides a compound pharmaceutical composition. Acacia celery extract and febuxostat are mixed, a pharmaceutically acceptable carrier or adjuvant is added, and compound pharmaceutical compositions such as tablets, capsules, granules and other solid dosage forms are further prepared. In the compound pharmaceutical composition, the weight ratio of celery locust extract to febuxostat is (225-2250): (5-20); the preferred ratio is (450-1800): (5-20), and more preferably The ratio is (900-1350):(5-20); the most preferred ratio is 900:(5-20).

As a preferred embodiment, the weight ratio of Acacia celery extract to febuxostat in the compound pharmaceutical composition is 900:5 or 900:10 or 900:20. It is further preferred that after giving the patient a medicinal composition with a weight ratio of celery locust extract and febuxostat of 900:20 for a period of time, the blood uric acid level is rapidly reduced to a reasonable level, and then the patient is given the celery locust extract and febuxostat. The pharmaceutical composition with the weight ratio of sestat being 900:10 keeps the blood uric acid level stable and does not rebound. For some patients with stable blood uric acid levels, the maintenance dose can be selected from the pharmaceutical composition of celery locust extract daily dose 900 mg + febuxostat daily dose 5 mg.

The extract of celery locust used in the present invention is prepared by the method described in the inventor’s previous Chinese patent application CN201610313303.8, and the ratio of celery seed and pagoda japonica in the extract of celery locust is 2:1–4:1.

The dosage form of the celery locust extract is preferably made into capsules (hereinafter referred to as celery locust capsules). As an embodiment, each capsule contains 100-300 mg, preferably 225 mg, of the celery locust extract. For febuxostat, commercially available tablets can be used, and the dose can be divided according to the specifications. It is further preferred to prepare small-dose febuxostat tablets specially to ensure accurate dosage.

When combined administration is used, the specific treatment plan of one embodiment is as follows:

Qinhuai Capsules + Febuxostat Tablets: Qinhuai Capsules (each based on extract: 225mg, 4 capsules per day, 2 capsules in the morning and evening) and Febuxostat Tablets (specification: 20mg, 1 tablet per day); After 4 weeks of implementation of the above treatment plan, it was adjusted to 4 capsules of Qinhuai Capsules per day, 2 capsules in the morning and evening + febuxostat tablets (specification: 20mg, half a tablet per day,) in combination.

After preclinical and preliminary clinical research, the inventor unexpectedly found that the combination or combination of Qinhuai Capsules and febuxostat has the following unexpected advantages:

1. The mechanism of action is superimposed

The mechanism of action of locust locust extract and febuxostat is through inhibiting the activity of xanthine oxidase, reducing uric acid synthesis and blood uric acid content, thereby reducing the deposition of urate in bones, joints and kidneys, and helping In the redissolution of gouty nodules and uric acid crystals. Therefore, the combined use of the two drugs makes it possible to reduce the dose of febuxostat due to the superposition of the mechanism of action.

2. The clinical effect is quick and long-lasting, and it also has the effect of dissolving kidney stones and tophi

(1) Quick effect

As mentioned above, celery locust extract is a pure traditional Chinese medicine preparation with mild effects. The advantage is that the sharp drop in blood uric acid in a short period of time will not destroy the uric acid balance between blood and tissues and induce acute gout; the disadvantage is that the onset of action is slow, and the patient's blood uric acid level is slow to reach the standard. After clinical research, it was found that the combination of Qinhuai Capsules and febuxostat can produce a moderate uric acid-lowering effect relatively quickly, and has a strong ability to control the temporary fluctuation of blood uric acid level caused by diet.

(2) lasting effect

Maintaining the blood uric acid level <360μmol/L is the key to the treatment of gout. After acid-lowering treatment, the blood uric acid concentration can reach the normal range, which is conducive to the dissolution of tophi and reduces the onset of gout, so as to effectively prevent various chronic diseases caused by hyperuricemia. damage. Clinical studies have shown that the combination of Acacia celery extract and a small dose of febuxostat can produce long-term and stable uric acid-lowering effect, and the fluctuation of blood uric acid is small. During the combined drug treatment, the blood uric acid level can be rapidly reduced, and at the same time, the urate deposited in the body can be quickly released, but it will not cause acute gout symptoms. Some patients with gout and hyperuricemia have been taking combined medication for up to 10 years, and the blood uric acid has always remained at a normal level. Moreover, in the long-term medication process, there are occasional acute gout attacks, and the symptoms are lighter than before, and the recovery period is also short, and the interval of onset is prolonged.

(3) Dissolving kidney stones and tophi

The deposition of urate in the kidney produces urate crystals and forms uric acid stones, leading to the occurrence and development of obstructive nephropathy and eventually end-stage renal disease. Usually 25% of gout patients have kidney stones, 200 times higher than normal. At present, shock wave lithotripsy and minimally invasive stone removal surgery have become the main means of clinical treatment of kidney stones, but they have not fundamentally reversed the cause of stone formation, and there is still a certain recurrence rate.

In addition, urate is easily deposited in the joints to form "tophi". Acute gout attacks can cause severe pain, which is unbearable. In severe cases, it can cause joint deformities, making it impossible to walk normally. Difficulty, if not treated in time, it will rupture on its own, the wound will not heal after years, and eventually amputation will be forced due to infection.

Clinical studies have shown that some gout patients with hyperuricemia can rapidly reduce blood uric acid levels after long-term combined use of celery locust extract and small doses of febuxostat. When the blood uric acid level drops, the deposition The balance of uric acid in the tissue causes uric acid to gradually dissolve from the tissue into the blood, causing the deposited uric acid to gradually dissolve and become smaller until it disappears. It can promote the gradual disintegration of uric acid stone crystals and has the effect of dissolving uric acid stones. It can restore joint flexibility and avoid deformation, deformity, disability and other conditions.

3. Significantly reduce toxic and side effects, suitable for long-term medication

In the field of gout treatment, the patient base is large, the growth rate is fast, and the market demand is broad. In the field of gout treatment, gout cannot be cured and requires life-long medication, so safety is particularly important. Most of the existing drugs have obvious defects in safety. Due to its high cardiovascular toxicity, febuxostat tablets have been downgraded to second-line drugs by the US gout treatment guidelines.

According to the inventor's clinical observation study, patients with gout and hyperuricemia were randomly divided into three groups, and the patients in the test group were combined with extract of celery locust tree (2 capsules/time, 2 times/day) and small dose of febuxostat (before 20mg/day for 4 weeks, and 10mg/day for the next 8 weeks), the control group was only treated with celery locust extract (2 capsules/time, 2 times/day) or high-dose febuxostat tablets (40mg/day), the course of treatment for 12 weeks. The results showed that there was no abnormality in the electrocardiogram examination of patients in the combined medication group and the Qinhuai capsule group alone, and only mild gastrointestinal adverse reactions were found. A small number of patients in the high-dose febuxostat group had abnormal electrocardiograms. It is suggested that the combination of Acacia celery extract and low-dose febuxostat can significantly reduce the cardiotoxicity of high-dose febuxostat tablets, which is convenient for long-term maintenance treatment of gout patients.

detailed description

The present invention will be further described below through specific examples, but it should be understood that these examples are only for clarifying the present invention, and do not limit the scope of the present invention in any form.

Experimental materials and instruments:

The sources of experimental materials are as follows:

The sources of experimental equipment are as follows:

High-speed mixing granulator: miniCG, Chuangzhi Electromechanical Technology Co., Ltd.

Swing pellet machine: YK-160, Jiangyin Kanghe Machinery Manufacturing Factory

Oven: DHG-9140A, Beijing Luxi Technology Co., Ltd.

Dry granulator: RCG100-25L, Chongqing Yingge Granulation Coating Technology Co., Ltd.

Fluidized bed: WBF-2G, Chongqing Yingge Granulation Coating Technology Co., Ltd.

High-speed granulator: YZLJ-125 type, Chuangzhi Electromechanical Technology Co., Ltd.

Hopper mixer: HSD5, Zhejiang Canaan Technology Co., Ltd.

Tablet press: ZPS016, Shanghai Tianxiang Jiantai Pharmaceutical Machinery Co., Ltd.

The preparation of embodiment 1 celery locust extract capsule

The Qinhuai capsules used in the following test examples can be prepared in the following manner.

(1) Prescription composition

The extract of celery locusts used in the present invention can be prepared by the method described in the inventor's previous Chinese patent application CN201610313303.8.

In the present embodiment, the ratio of celery seed and sophora japonica in the celery locust extract is 3:1, and the operation is as follows:

Take 15 kg of celery seeds and 5 kg of Sophora japonica, add 10 times the weight of 60% (V/V) ethanol aqueous solution at 50-60° C. to extract 3 times, each time for 60 minutes. The extracts were combined, concentrated under reduced pressure, and dried in vacuum to obtain 480 g of the extract of the present invention.

(2) Preparation process

Solution preparation: Weigh the polysorbate 80 of prescription quantity, dissolve in appropriate amount of absolute ethanol, set aside.

Acid-making granules: Weigh tartaric acid, low-substituted hydroxypropyl cellulose and lactose, place them in a high-speed mixing granulator, and mix for 5 minutes; add the polysorbate 80 absolute ethanol solution prepared above, stir for 3 minutes, and discharge. Pour into a swinging granulator, granulate with a 20-mesh sieve, and dry in an oven at 55°C.

Blending: Put the prescription amount of celery extract, hydroxypropyl beta cyclodextrin, sodium bicarbonate and the acid granules prepared above in a high-speed mixer and mix for 5 minutes; then add magnesium stearate and continue mixing for 5 minutes , the material is ready for use.

Dry granulation: Add the blended granules prepared above to a dry granulator for granulation.

Encapsulation: Take the zero-size capsule and fill it with the above-mentioned dry granulated granules to obtain the product. Each capsule contains 225mg of celery locust extract.

The preparation of embodiment 2 febuxostat tablet

The febuxostat tablets used in the following test examples, 20 mg, can be commercially available, or can be prepared in the following manner.

Preparation of febuxostat tablets (specifications: 5mg, 10mg, 20mg):

(1) Prescription composition

(2) Preparation process

The 3 specifications are prepared according to the following process:

Fluidized bed granulation: put the prescribed amount of febuxostat, lactose monohydrate, pregelatinized starch, and hydroxypropyl cellulose in the fluidized bed, the air inlet temperature is 60°C, and granulate in one step, and the dry granules are sized at high speed Machine granulation.

Mixing: the granules prepared above are mixed with the prescription amount of lactose and croscarmellose sodium in a hopper mixer; the prescription amount of magnesium stearate is weighed and added to the materials for total mixing.

Tablet compression: Transfer the blended granules prepared above to the hopper of a tablet press (ZPS016 Shanghai Tianxiang Jiantai Pharmaceutical Machinery Co., Ltd.) for tablet compression.

Embodiment 3 comprises the compound preparation of celery locust extract and febuxostat

Preparation of capsules of celery locust extract 225mg + febuxostat 1.25mg, 2.5mg, 5mg.

(1) Prescription

In Example 3-1, the ratio of celery seed and Sophora japonica in the extract of celery locust is 2:1, the ratio of Example 3-2 is 3:1, and the ratio of Example 3-3 is 4:1, prepared by the following process :

Take celery seed and Sophora japonica according to the weight ratio, add 10 times the weight of 60% (V/V) ethanol aqueous solution at 50-60° C. to extract 3 times, each time for 60 minutes. The extracts were combined, concentrated under reduced pressure, and dried in vacuum to obtain the extract of Acacia celery used in the present invention.

(2) Preparation process

The 3 specifications are prepared according to the following process:

Solution preparation: Weigh the prescribed amount of polysorbate 80, dissolve in an appropriate amount of absolute ethanol, and set aside.

Preparation of acid granules containing febuxostat: Weigh febuxostat, tartaric acid, low-substituted hydroxypropyl cellulose and lactose, place them in a high-speed mixing granulator, start the mixing granulator, and stir for 5 minutes; add the above-prepared The polysorbate 80 absolute ethanol solution was stirred for 3 minutes, discharged, poured into a swinging granulator, granulated with a 20-mesh sieve, and dried in an oven at 55°C.

Total mixing: put the prescription amount of celery extract, hydroxypropyl beta cyclodextrin, sodium bicarbonate and magnesium stearate in a high-speed mixer, start the mixer, and mix for 5 minutes; add the acid granules prepared above , continue mixing for 5 minutes, stop stirring, and discharge for later use.

Dry granulation: Add the blended granules prepared above to a dry powder granulator for dry granulation.

Encapsulation: Take the zero-size capsule and fill it with the above-mentioned dry granulated granules to obtain the product.

Take 4 capsules per day, which is equivalent to the daily dose of celery extract 900mg + febuxostat dose 5mg or the daily dose of celery extract 900mg + febuxostat dose or the daily dose of celery extract 900mg + febuxostat dose 20 mg.

Test Example 1 Animal Test Data

Experimental Materials

Test product information:

The extract of celery locust was prepared according to Example 1, and the ratio of celery seed and sophora japonica in the celery locust extract was 3:1. Sealed and protected from light, stored in a dry place at room temperature.

Positive drug information:

Febuxostat tablets, manufacturer: Japan TEIJIN PHARMA LIMITED. Specification: 20mg; batch number: 6484, valid until February 2022. Keep airtight at no more than 25°C.

Detection kit:

Uric acid detection kit: Zhongsheng Beikong Biotechnology Co., Ltd., batch number: 19251.

Solvent:

0.5% CMC-Na aqueous solution; CMC-Na batch number: 20190123, Sinopharm Chemical Reagent Co., Ltd.

experimental method

Male SD rats (provided by Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.) were selected for the experiment. They were randomly divided into normal group and model group according to body weight. The normal group (10 rats) was given normal diet and drinking water; the model group (280 rats) was given normal diet and 10% fructose aqueous solution. After successful modeling, the rats in the model group were randomly divided into 10 rats in each group, including 1 rat in the model control group and 27 rats in the experimental group. The normal group and the model control group were given 0.5% CMC-Na aqueous solution for intragastric administration, and the remaining groups were administered by intragastric administration according to the corresponding drug dissolved in 0.5% CMC-Na aqueous solution (ultrasonic dissolution). Once, administration for 28 days. Before administration and 28 days after administration, the blood uric acid (SUA) level was detected by biochemical method.

According to the dosage process of Qinhuai capsules (225mg per capsule) converted from human to animal is as follows:

Based on the daily dose of Qinhuai Capsules for humans being 1 to 10 capsules, the dose converted into rats is 225mg×0.018/0.2kg=20.25mg/kg to 225mg×10 capsules×0.018/0.2kg=202.5mg/kg.

The dose conversion process of febuxostat from human to animal is as follows:

Based on the daily dose of febuxostat at 10mg-40mg, the dose converted into rats is 10mg×0.018/0.2kg=0.9mg/kg to 40mg×0.018/0.2kg=3.6mg/kg.

The dosage of each experimental group is shown in the following table 1:

Dosage of each experimental group in table 1

Note: The dose of celery locust extract group is equivalent to the human dose equivalent to the number of celery locust capsules (specification 225mg): A1: 1 capsule; A2: 2 capsules; A3: 4 capsules; A4: 6 capsules; A5: 8 capsules ; A6: 10 capsules; the dose of febuxostat group equivalent to the human dose is equivalent to B1: 10 mg; B2: 20 mg; B3: 40 mg.

Experimental results: see Table 2.

Table 2 The effect of Qinhuai Capsules combined with febuxostat tablets on blood uric acid levels in hyperuricemia rats (μmol/L,

n=10)

Note: The above data are the mean value of 10 rats in each group.

Experimental data show that:

1. As the dose of celery locust extract increases, the effect of reducing blood uric acid level increases, but the degree of increase in high doses is less than that in low doses.

2. As the dose of febuxostat increases, the effect increases, and the effect of large doses is stronger, but the side effects begin to appear obviously.

3. When the two are administered together, the synergistic effect is not obvious due to the small dose of celery locust extract in group A1+B1 and A1+B2 group, and the excessive dose of celery locust extract in group A6+B1 and A6+B2 , the synergistic effect is not obvious, and the middle dose has obvious synergistic effect. Compared with the model group, the reduction effect of the blood uric acid level in the combination group is greater than the sum of the effects of the two single drugs administered separately, and there is an obvious synergistic effect.

4. When the dose of febuxostat was large, no synergistic effect was found from the A1+B3 group to the A6+B3 group. It was speculated that the synergistic effect of the whole group was not due to the strong effect of the large dose of febuxostat. exist.

The observation of test example 2 clinical effect

1. Purpose of observation

As mentioned above, while febuxostat single drug produces uric acid-lowering effect at conventional doses, it is also accompanied by strong side effects, especially cardiovascular toxicity, which can be fatal in severe cases. In view of this, on the basis of the patient's willingness, a treatment plan for the combination of Qinhuai Capsules and low-dose febuxostat was developed, and Qinhuai capsules were taken orally or combined with small-dose febuxostat tablets to investigate the effectiveness of treating gout with hyperuricemia. sex and safety.

2. Cases of patients

Number of people: 30 cases. They were randomly divided into 3 groups, 10 cases in each group.

Gender: 24 males and 6 females, including 5 patients with high uric acid and 25 patients with gout diagnosed by the hospital (21 males and 4 females).

Age range: 18-70 years old

3. Dose Design

1. Group 1 (Qinhuai capsule group): 4 capsules per day, 2 capsules in the morning and evening.

2. Group 2 (combined use of Qinhuai Capsules and small-dose febuxostat tablets): the initial dose is 4 capsules per day, 2 capsules in the morning and evening + 1 febuxostat tablet (specification: 20mg) per day . After one month, depending on the level of uric acid, continue to reduce the dosage of febuxostat, and adjust it to 4 capsules of Qinhuai capsules per day, 2 capsules in the morning and evening + half a tablet of febuxostat (specification: 20mg) per day. After 1 month, depending on the level of uric acid, continue the maintenance treatment.

3. Group 3 (high-dose febuxostat tablet group): the initial dose is 20 mg/day, once/day. After 1 month, gradually increase the dosage according to the blood uric acid value, each increment is 20mg, and the maximum daily dose is 80mg.

4. Curative Effect Observation Results

There was no significant difference in blood uric acid value before treatment among the three groups (p>0.05). After 1, 2, and 3 months of treatment, the blood uric acid value of the combined drug group was significantly lower than that of the Qinhuai capsule group alone (p<0.05), and there was no significant difference from the high-dose febuxostat group (p>0.05), see table 3.

Table 3 Comparison of blood uric acid values at each time point among the three groups (μmol/L,

n=10)

Note 1: *Compared with Group 2, there is a significant difference (p<0.05);^#Compared with Group 2, there is no significant difference (p<0.05)

Note 2: The above data are the mean value of 10 patients in each group.

5. Observation results of adverse reactions

After 3 months of continuous oral administration, only 2 patients in the Qinhuai Capsules group had adverse reactions in the gastrointestinal tract on the second day of administration. There was a transient burning sensation in the stomach, which disappeared after continued medication without treatment.

One patient in the Qinhuai capsule + low-dose febuxostat group had mild flatulence on the 5th day after administration, and the symptoms disappeared on the 2nd day without stopping the drug.

In the high-dose febuxostat group, 1 patient developed stomach discomfort in the 2nd month after administration; 2 patients had abnormal electrocardiograms in the 3rd month, 2 patients had abnormal liver function, 1 patient had Abnormal renal function, see Table 4.

Table 4 adverse reaction observation results

6. Summary and discussion

Many years of clinical research at home and abroad have shown that febuxostat is an effective drug for lowering uric acid, but the safety of the drug has attracted attention, especially because of the cardiovascular toxicity of febuxostat, it is difficult for patients with gout and hyperuricemia Adhere to long-term medication. Some gout patients would rather endure severe pain than take medicine because they are afraid of the adverse reactions of gout medicine.

In order to reduce the toxic and side effects of febuxostat and continue to exert the clinical value of the old drug, Qinhuai Capsules and small doses of febuxostat were combined for 3 months to observe whether there is a significant effect of lowering uric acid and adverse reactions Whether it declines, focus on observing the adverse reactions of febuxostat. The control group received Qinhuai Capsules or high-dose febuxostat tablets alone.

Results: The trial enrolled 30 patients, among whom the gout patients all suffered from gout attacks due to the lack of timely and standardized treatment of hyperuricemia. In the clinical trial, the patients were divided into three groups, the first group was Qinhuai Capsules alone, the second group was Qinhuai Capsules combined with low-dose febuxostat tablets, and the third group was large-dose febuxostat tablets alone. Dose febuxostat group.

After 3 months of treatment, it was pleasantly discovered that the combined use of Qinhuai Capsules and small doses of febuxostat has significantly better uric acid-lowering effect than single use of Qinhuai Capsules, and there is no significant difference from single use of large doses of febuxostat. The combination of the two drugs has a synergistic effect of lowering uric acid.

In terms of safety, only one patient in the combination group of Qinhuai Capsules and low-dose febuxostat experienced mild flatulence, and the symptoms disappeared on the second day without stopping the drug. However, patients in the high-dose febuxostat group experienced stomach discomfort, abnormal electrocardiogram, abnormal liver function, and abnormal renal function, which were consistent with literature reports and within the expected range. After taking Qinhuai Capsules alone, only one patient experienced a mild transient burning sensation in the stomach, and the uric acid-lowering effect was weaker than that of the combined medication, which was also within the expected range.

Summary: Qinhuai Capsules are combined with low-dose febuxostat tablets. In this clinical trial, 30 patients with gout and hyperuricemia were enrolled, and the combination of Qinhuai Capsules and low-dose febuxostat tablets was compared and observed. The curative effect and safety of the drug on patients with hyperuricemia and gout were compared with Qinhuai Capsule alone and high-dose febuxostat tablets. The results show that the combination of Qinhuai Capsules and small doses of febuxostat tablets has excellent curative effect and safety, which reduces the possible toxic and side effects of febuxostat tablets in large doses, especially in patients with heart disease without febuxostat tablets. Toxicity and other adverse reactions are more suitable for long-term maintenance medication for patients with gout and hyperuricemia. This is a breakthrough in the field of gout treatment and provides preliminary experimental data for large-scale clinical trials in the future.

In addition, in the combination group, it was also found that the kidney stones of one patient disappeared after 3 months of treatment. After the end of the 3-month research experiment, the 3 patients with stable blood uric acid levels were treated with a combination of 900 mg daily dose of celery locust extract + 5 mg febuxostat daily dose to continue the maintenance phase of treatment, and the blood uric acid levels remained reasonable for a long time Level.

Embodiment 4 combination kit

This combination kit includes:

1. Acacia extract is used as a capsule of active substance, and each capsule contains 225mg of Acacia extract.

2. Febuxostat tablet, specification 5mg.

The ratio of the number of capsules of celery locust extract as the active substance to the number of febuxostat tablets is 2:1 or 4:1, or 6:1 or 8:1.

3. Instructions for use of the drug, which state that when the combination kit is used, the patient takes 5 mg (1 tablet) febuxostat tablet every day, and the number of capsules of celery extract capsules to be taken daily is selected from 2, 4, or 6 or 8.

Embodiment 5 combination kit

This combination kit includes:

2. Febuxostat capsules, specification 10mg.

The ratio of the number of capsules of celery locust extract as the active substance to the number of febuxostat capsules is 2:1 or 4:1, or 6:1 or 8:1.

3. Instructions for use of the drug, which state that when the combination kit is used, the patient takes one febuxostat capsule per day, and the number of capsules of celery extract capsules per day is selected from 2, 4, 6 or 8 .

Embodiment 6 combination kit

This combination kit includes:

2. Febuxostat tablet, specification 20mg.

3. Instructions for use of the drug, which state that when the combination kit is used, the patient takes one febuxostat tablet per day, and the number of celery extract capsules per day is selected from 2, 4, 6 or 8.

Claims

A pharmaceutical composition of celery locust extract and febuxostat for treating both symptoms and root causes of gout, characterized in that the pharmaceutical composition consists of 225-2250mg celery locust extract, 5-20mg febuxostat and pharmaceutically acceptable The carrier composition, wherein the celery locust extract is celery seed and sophora japonica alcohol extract with a weight ratio of 2:1-4:1.
The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is selected from:

The pharmaceutical composition is composed of 450-1800mg of celery locust extract, 10-20mg of febuxostat and a pharmaceutically acceptable carrier, wherein the celery locust extract is celery with a weight ratio of 2:1-4:1 Alcohol extracts of seeds and Sophora japonica; or

The pharmaceutical composition is composed of 900-1350mg celery locust extract, 10-20mg febuxostat and a pharmaceutically acceptable carrier, wherein the celery locust extract is celery with a weight ratio of 2:1-4:1 Seed and Sophora Alcohol Extract.
A medicine kit for treating gout and/or hyperuricemia in mammals or humans, characterized in that the medicine kit consists of 225-2250 mg celery locust extract, 5-20 mg febuxostat, pharmaceutically acceptable carrier and medicine The instructions are composed, wherein the extract of celery locust is the alcohol extract of celery seed and sophora japonica with a weight ratio of 2:1-4:1.
The kit according to claim 3, characterized in that the kit is selected from:

The kit consists of 450-1800mg of celery locust extract, 10-20mg of febuxostat, a pharmaceutically acceptable carrier and drug instructions, wherein the celery locust extract is celery with a weight ratio of 2:1-4:1 Seeds and Sophora japonica alcohol extract; or, the kit is composed of 900-1350mg celery locust extract, 10-20mg febuxostat and a pharmaceutically acceptable carrier and drug instructions, wherein the celery locust extract is a weight ratio of 2:1-4:1 alcohol extracts of celery seed and sophora.
The kit according to claim 3 or 4, characterized in that the extract of Acacia celery in the kit is granules, tablets, dropping pills, or capsules made by adding a pharmaceutically acceptable carrier, febux It is a tablet or capsule made by adding pharmaceutically acceptable carriers.
The use of a pharmaceutical composition of celery locust extract and febuxostat in the preparation of medicines for treating gout and/or hyperuricemia in mammals or humans, wherein the pharmaceutical composition consists of 225-2250mg celery locust extract, 5 - Composition of 20mg of febuxostat and a pharmaceutically acceptable carrier, wherein the celery extract is celery seed and sophora japonica alcohol extract with a weight ratio of 2:1-4:1.
The purposes of the combination of a kind of celery locust extract and febuxostat in the preparation treatment mammalian or human gout and/or hyperuricemia medicine, wherein said celery locust extract is that weight ratio is 2:1-4: 1 of celery seed and sophora japonica alcohol extract, preferably the daily dose range of febuxostat is 5 mg to 20 mg, and the daily dose range of celery locust extract is 225 mg to 2250 mg in terms of extract.
A use of acacia extract in the preparation of a drug for improving the therapeutic effect of febuxostat on gout and/or hyperuricemia and/or reducing its toxic and side effects, wherein the extract of acacia is weight ratio It is 2:1-4:1 celery seed and sophora japonica alcohol extract, preferably, the daily dose range of the febuxostat tablet is 5 mg to 20 mg, the daily dose range of the celery locust extract in terms of extract From 225mg to 2250mg.
The use according to claim 7 or 8, wherein the Acacia celery extract and febuxostat are administered simultaneously, successively or separately.
A pharmaceutical composition of celery locust extract and febuxostat, which is used for treating gout and/or hyperuricemia in mammals or humans.
A method for treating gout and/or hyperuricemia in mammals or humans with combination therapy of acacia extract and febuxostat, comprising administering an effective dose of acacia extract and febuxostat to a patient, febuxostat The daily dose range of the tablet is 5 mg to 20 mg, and the daily dose range of the extract of celery locust is 225 mg to 2250 mg in terms of extract.